Clinical Pharmacokinetics of Oxcarbazepine

Abstract

Oxcarbazepine is an antiepileptic drug with a chemical structure similar to carbamazepine, but with different metabolism. Oxcarbazepine is rapidly reduced to 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD), the clinically relevant metabolite of oxcarbazepine. MHD has (S)-(+)- and the (R)-(-)-enantiomer, but the pharmacokinetics of the racemate are usually reported. The bioavailability of the oral formulation of oxcarbazepine is high (>95%). It is rapidly absorbed after oral administration, reaching peak concentrations within about 1-3 hours after a single dose, whereas the peak of MHD occurs within 4-12 hours. At steady state, the peak of MHD occurs about 2-4 hours after drug intake. The plasma protein binding of MHD is about 40%. Cerebrospinal fluid concentrations of MHD are in the same range as unbound plasma concentrations of MHD. Oxcarbazepine can be transferred significantly through the placenta in humans. Oxcarbazepine and MHD exhibit linear pharmaco-kinetics and no autoinduction occurs. Elimination half-lives in healthy volunteers are 1-5 hours for oxcarbazepine and 7-20 hours for MHD. Longer and shorter elimination half-lives have been reported in elderly volunteers and children, respectively. Mild to moderate hepatic impairment does not appear to affect MHD pharmacokinetics. Renal impairment affects the pharmacokinetics of oxcarbazepine and MHD. The interaction potential of oxcarbazepine is relatively low. However, enzyme-inducing antiepileptic drugs such as phenytoin, phenobarbital or carbamazepine can reduce slightly the concentrations of MHD. Verapamil may moderately decrease MHD concentrations, but this effect is probably without clinical relevance. The influence of oxcarbazepine on other antiepileptic drugs is not clinically relevant in most cases. However, oxcarbazepine appears to increase concentrations of phenytoin and to decrease trough concentrations of lamotrigine and topiramate. Oxcarbazepine lowers concentrations of ethinylestra-diol and levonorgestrel, and women treated with oxcarbazepine should consider additional contraceptive measures. Due to the absent or lower enzyme-inducing effect of oxcarbazepine, switching from carbamazepine to oxcarbazepine can result in increased serum concentrations of comedication, sometimes associated with adverse effects. The effect of oxcarbazepine appears to be related to dose and to serum concentrations of MHD. In general, daily fluctuations of MHD concentration are relatively slight, smaller than would be expected from the elimination half-life of MHD. However, relatively high fluctuations can be observed in individual patients. Therapeutic monitoring may help to decide whether adverse effects are dependent on MHD concentrations. A mean therapeutic range of 15-35 mg/L for MHD seems to be appropriate. However, more systematic studies exploring the concentration-effect relationship are required.

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

“…References for drugs whose half-lives are altered in patients receiving liver enzyme inducers: felbamate [36], lamotrigine [37], oxcarbazepine [38], rufinamide [39], tiagabine [40], topiramate [41] and zonisamide [15]. b Half-life increases to 30–90 h during concomitant therapy with valproic acid (enzyme inhibitor).…”

“…Oxcarbazepine is structurally related to carbamazepine but does not produce nearly as much induction of liver enzymes as carbamazepine and also shows a lower incidence of agranulocytosis [38,121]. Oxcarbazepine is rapidly and completely absorbed [38] and metabolized via 10-keto reduction to its monohydroxy derivative 10-hydroxycarbazepine.…”

“…Oxcarbazepine is rapidly and completely absorbed [38] and metabolized via 10-keto reduction to its monohydroxy derivative 10-hydroxycarbazepine. 10-Hydroxycarbazepine has equal potency to oxcarbazepine in antiseizure activity, but accumulates to higher concentrations in serum [122].…”

“…There is little data on the effect of hemodialysis on oxcarbazepine or 10-hydroxycarbazepine except for a case report of the successful treatment of massive oxcarbazepine overdose by hemodialysis [125]. The clearance of 10-hydroxycarbazepine is increased in pregnancy [126] and in patients taking liver enzyme-inducing drugs [38]. Young children require higher doses of oxcarbazepine per body weight than adults [127].…”

Lack of Pharmacokinetic Interaction between Oxcarbazepine and Lamotrigine

“…Two reports indicate that induction of glucuronidation pathways by oxcarbazepine may affect the metabolism of lamotrigine (May et al, 1999;Kramer et al, 2003) and another describes higher MHD concentrations in the presence of lamotrigine compared to oxcarbazepine monotherapy (Guenault et al, 2003). Drug interactions may also be theoretically possible due to the potential inhibition of glucuronidation, which is the first-step of the metabolism and excretion pathway of the active metabolite of oxcarbazepine 10-monohydroxy (MHD) (May et al, 2003) as well as the most important metabolic transformation inactivating lamotrigine (Cohen et al, 1987;Lloyd et al, 1994).…”